Polyketides constitute a large and highly diverse group of secondary metabolites synthesized by bacteria, fungi and plants, with a broad range of biological activities and medical applications. They include anti-cancer agents (Daunorubicin), antibiotics (tetracyclines, erythromycin etc.), immunosuppressants (macrolide FK506) and compounds with mycotoxic activity (aflatoxins, ochratoxins, ergochromes, patulin etc.). Polyketides are synthesized by repetitive condensations of acetate or propionate monomers in a similar way to that of fatty acid biosynthesis. Structural diversity of polyketides is achieved through different thioester primers, varying chain extension units used by the polyketide synthases (PKSs), and variations in the stereochemistry and the degree of reduction of intermediates. Diversity is also achieved by subsequent processing, such as alkylations, oxidations, O-methylations, glycosylations and cyclizations. Genetic studies indicated that gene organization of functional units and motif patterns of various PKSs are similar. This similarity was used to identify and obtain new PKS systems in both gram negative and gram positive bacteria.
PKS systems are classified into two types: type I PKSs are large, multifunctional enzymes, containing a separate site for each condensation or modification step. These represent “modular PKSs” in which the functional domains encoded by the DNA sequence are usually ordered parallel to the sequence of reactions carried out on the growing polyketide chain. Type II PKSs are systems made up of individual enzymes, in which each catalytic site is used repeatedly during the biosynthetic process.
Genetic studies on prokaryotic PKSs have focused on gram positive microorganisms, particularly on actinomycetes. Myxobacteria are gram negative bacteria that produce a large number of secondary metabolites, including polyketides. Myxococcus xanthus produces TA (Rosenberg, et al., 1973; Rosenberg. et al., 1984), which is an antibacterial antibiotic.
The polyketide antibiotic Tel-Aviv (hereinafter TA) (Rosenberg, et al., 1973) is synthesized by the gram negative bacterium Myxococcus xanthus in a unique multi-step process incorporating a glycine molecule into the polyketide carbon chain, which is elongated through the condensation of 11 acetate molecules by a type I polyketide synthase PKSs).
The antibiotic TA was crystallized and its chemical properties were determined. It is a macrocyclic polyketide synthesized through the incorporation of acetate, methionine, and glycine. It inhibits cell wall synthesis by interfering with the polymerization of the lipid-disaccharide-pentapeptide and its ability to adhere avidly to tissues and inorganic surfaces makes it potentially useful in a wide range of clinical applications, such as treating gingivitis.
A growing interest in the study of PKS systems and peptide synthetase systems stems from the need to develop new potent biologically active compounds. The use of combinatorial genetics in both systems (PKS and peptide synthetase) separately has led to the production of new polyketides and new peptides.
It would therefore by useful to be able to generate new biological agents from secondary metabolites of the antibiotic TA.